Initial diagnosis of the congenital disorder of glycosylation PMM2-CDG (CDG1a) in a 4-year-old girl after neurosurgical intervention for cerebral hemorrhage

Stefanits, Harald; Konstantopoulou, Vassiliki; Kuess, Magnus; Milenković, Ivan; Matula, Christian

doi:10.3171/2014.7.peds14102

Cited by 13 publications

(11 citation statements)

References 24 publications

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“…The pathogenesis of this coagulation dysfunction is complex, likely comprising impaired hepatic synthesis or protein excretion, rapid clearance, weak activity due to hypoglycosylation, and platelet dysfunction due to hypoglycosylation of membrane glycoproteins. [35][36][37][38] In this study, AZA treatment significantly increased prothrombin time, coagulation factor X, and antithrombin, despite a decrease in pH. Recent literature shows that AZA is a potent antithrombotic in vivo, although the signaling pathway involved might include the regulation of reactive oxygen species; however, at the moment, there is no evidence in the literature of this effect.…”

Section: Discussioncontrasting

confidence: 52%

“…[35][36][37][38] In this study, AZA treatment significantly increased prothrombin time, coagulation factor X, and antithrombin, despite a decrease in pH. The pathogenesis of this coagulation dysfunction is complex, likely comprising impaired hepatic synthesis or protein excretion, rapid clearance, weak activity due to hypoglycosylation, and platelet dysfunction due to hypoglycosylation of membrane glycoproteins.…”

Section: Discussionmentioning

confidence: 54%

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AZATAX: Acetazolamide safety and efficacy in cerebellar syndrome in PMM2 congenital disorder of glycosylation (PMM2‐CDG)

Martinez‐Monseny¹,

Bolasell²,

Callejón‐Póo³

et al. 2019

Annals of Neurology

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Objective: Phosphomannomutase deficiency (PMM2 congenital disorder of glycosylation [PMM2-CDG]) causes cerebellar syndrome and strokelike episodes (SLEs). SLEs are also described in patients with gain-of-function mutations in the CaV2.1 channel, for which acetazolamide therapy is suggested. Impairment in N-glycosylation of CaV2.1 promotes gain-of-function effects and may participate in cerebellar syndrome in PMM2-CDG. AZATAX was designed to establish whether acetazolamide is safe and improves cerebellar syndrome in PMM2-CDG. Methods: A clinical trial included PMM2-CDG patients, with a 6-month first-phase single acetazolamide therapy group, followed by a randomized 5-week withdrawal phase. Safety was assessed. The primary outcome measure was improvement in the International Cooperative Ataxia Rating Scale (ICARS). Other measures were the Nijmegen Pediatric CDG Rating Scale (NPCRS), a syllable repetition test (PATA test), and cognitive scores. Results: Twenty-four patients (mean age = 12.3 AE 4.5 years) were included, showing no serious adverse events. Thirteen patients required dose adjustment due to low bicarbonate or asthenia. There were improvements on ICARS (34.9 AE 23.2 vs 40.7 AE 24.8, effect size = 1.48, 95% confidence interval [CI] = 4.0-7.6, p < 0.001), detected at 6 weeks in 18 patients among the 20 responders, on NPCRS (95% CI = 0.3-1.6, p = 0.013) and on the PATA test (95% CI = 0.5-3.0, p = 0.006). Acetazolamide improved prothrombin time, factor X, and antithrombin. Clinical severity, epilepsy, and lipodystrophy predicted greater response. The randomized withdrawal phase showed ICARS worsening in the withdrawal group (effect size = 1.46, 95% CI = 2.65-7.52, p = 0.001). Interpretation: AZATAX is the first clinical trial of PMM2-CDG. Acetazolamide is well tolerated and effective for motor cerebellar syndrome. Its ability to prevent SLEs and its long-term effects on kidney function should be addressed in future studies. ANN NEUROL 2019;85:740-751 View this article online at wileyonlinelibrary.com.

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Section: Discussioncontrasting

confidence: 52%

Section: Discussionmentioning

confidence: 54%

AZATAX: Acetazolamide safety and efficacy in cerebellar syndrome in PMM2 congenital disorder of glycosylation (PMM2‐CDG)

Martinez‐Monseny¹,

Bolasell²,

Callejón‐Póo³

et al. 2019

Annals of Neurology

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“…Patients with CDG-1a can be divided into four stages by ages: infantile multisystemic disability, childhood ataxia-intellectual disability, teenage leg atrophy disability, and adulthood stable disability. In the first stage of CDG-1a, two distinct clinical forms are important to note: non-fatal neurologic form and neurologic-multivisceral [ 4 ]. The first one is characterized by strabismus, psychomotor retardation, hypotonia, and cerebellar hypoplasia, besides that, inverted nipples, abnormal fat distribution, and feeding problems are common in this form.…”

Section: Introductionmentioning

confidence: 99%

Atrial septal defect in a patient with congenital disorder of glycosylation type 1a: a case report

Tang

et al. 2018

J Med Case Reports

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BackgroundAtrial septal defect often become more severe when encountered in genetic syndromes. Congenital disorder of glycosylation type 1a is an inherited metabolic disorder associated with mutations in PMM2 gene and can affect almost all organs. Cardiac abnormalities vary greatly in congenital disorder of glycosylation type 1a and congenital heart defects have already been reported, but there is little knowledge about the effect of this inherited disorder on an existing congenital heart defect. Herein we report for the first time on a baby with congenital disorder of glycosylation type 1a with atrial septal defect and make a comparison of changes in atrial septal defect by follow-ups to the age of 3.Case presentationOur patient was an 8-month-old Han Chinese boy. At the initial visit, he presented with recurrent lower respiratory infection, heart murmur, psychomotor retardation, inverted nipples, and cerebellar atrophy. Echocardiography revealed a 8 mm secundum atrial septal defect with left-to-right shunt (Qp/Qs ratio 1.6). Enzyme testing of phosphomannomutase 2 demonstrated decreased levels of phosphomannomutase 2 activities in fibroblasts. Whole exon sequencing showed he was heterozygous for a frameshift mutation (p.I153X) and a missense mutation (p.I132T) in PMM2 gene. The diagnosis of congenital disorder of glycosylation type 1a with atrial septal defect was issued. Now, he is 3-years old at the time of this writing, with the development of congenital disorder of glycosylation type 1a (cerebellar atrophy become more severe and the symptom of nystagmus emerged), the size of atrial septal defect increased to 10 mm and the Qp/Qs ratio increased to 1.9, which suggested exacerbation of the atrial septal defect. Congenital heart defect-associated gene sequencing is then performed and shows there are no pathogenic mutations, which suggested intrinsic cardiac factors are not the cause of exacerbation of the atrial septal defect in our patient and it is reasonable to assume congenital disorder of glycosylation type 1a can worsen the situation of the existing atrial septal defect.ConclusionsThis report highlights the view that congenital disorders of glycosylation type 1a should be excluded when faced with congenital heart defect with cerebellar atrophy or neurodevelopmental delay, especially when the situation of congenital heart defect becomes more and more severe.

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“…Individuals with CDG-Ia present with a spectrum of neurological symptoms ( Jaeken, 2013 ), ranging from severe neurological impairments with early death, to mild defects with slight psychomotor delay ( Grünewald, 2009 ; Marquardt and Denecke, 2003 ). To date, no effective treatments are available, with the only treatment option being symptom management ( Grünewald, 2009 ; Monin et al, 2014 ; Stefanits et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

Synaptic roles for phosphomannomutase type 2 in a new Drosophila congenital disorder of glycosylation disease model

Parkinson

Dookwah

Dear

et al. 2016

Disease Models &Amp; Mechanisms

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Congenital disorders of glycosylation (CDGs) constitute a rapidly growing family of human diseases resulting from heritable mutations in genes driving the production and modification of glycoproteins. The resulting symptomatic hypoglycosylation causes multisystemic defects that include severe neurological impairments, revealing a particularly critical requirement for tightly regulated glycosylation in the nervous system. The most common CDG, CDG-Ia (PMM2-CDG), arises from phosphomannomutase type 2 (PMM2) mutations. Here, we report the generation and characterization of the first Drosophila CDG-Ia model. CRISPR-generated pmm2-null Drosophila mutants display severely disrupted glycosylation and early lethality, whereas RNAi-targeted knockdown of neuronal PMM2 results in a strong shift in the abundance of pauci-mannose glycan, progressive incoordination and later lethality, closely paralleling human CDG-Ia symptoms of shortened lifespan, movement impairments and defective neural development. Analyses of the well-characterized Drosophila neuromuscular junction (NMJ) reveal synaptic glycosylation loss accompanied by defects in both structural architecture and functional neurotransmission. NMJ synaptogenesis is driven by intercellular signals that traverse an extracellular synaptomatrix and are co-regulated by glycosylation and matrix metalloproteinases (MMPs). Specifically, trans-synaptic signaling by the Wnt protein Wingless (Wg) depends on the heparan sulfate proteoglycan (HSPG) co-receptor Dally-like protein (Dlp), which is regulated by synaptic MMP activity. Loss of synaptic MMP2, Wg ligand, Dlp co-receptor and downstream trans-synaptic signaling occurs with PMM2 knockdown. Taken together, this Drosophila CDG disease model provides a new avenue for the dissection of cellular and molecular mechanisms underlying neurological impairments and is a means by which to discover and test novel therapeutic treatment strategies.

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Initial diagnosis of the congenital disorder of glycosylation PMM2-CDG (CDG1a) in a 4-year-old girl after neurosurgical intervention for cerebral hemorrhage

Cited by 13 publications

References 24 publications

AZATAX: Acetazolamide safety and efficacy in cerebellar syndrome in PMM2 congenital disorder of glycosylation (PMM2‐CDG)

AZATAX: Acetazolamide safety and efficacy in cerebellar syndrome in PMM2 congenital disorder of glycosylation (PMM2‐CDG)

Atrial septal defect in a patient with congenital disorder of glycosylation type 1a: a case report

Synaptic roles for phosphomannomutase type 2 in a new Drosophila congenital disorder of glycosylation disease model

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